Even though differentiated thyroid carcinoma is a slow growing and usually curable disease, recurrence occurs in 20-40% and cellular dedifferentiation in up to 5% of cases. Conventional chemotherapy and radiotherapy have just a modest effect on advanced thyroid cancer. Therefore, dedifferentiated thyroid cancer represents a therapeutic dilemma and a critical area of research. Targeted therapy, a new generation of anticancer treatment, is planned to interfere with a specific molecular target, typically a protein that is believed to have a critical role in tumor growth or progression. Since many of the tumor-initiation events have already been identified in thyroid carcinogenesis, targeted therapy is a promising therapeutic tool for advanced thyroid cancer. Several new drugs are currently being tested in in vitro and in vivo studies and some of them are already being used in clinical trials, like small molecule tyrosine kinase inhibitors. In this review, we discuss the bases of targeted therapies, the principal drugs already tested and also options of redifferentiation therapy for thyroid carcinoma.

Iodine is a trace element that is essential for the synthesis of thyroid hormone. Both chronic iodine deficiency and iodine excess have been associated with hypertrophy and hyperplasia of follicular cells, attributed to excessive secretion of TSH. This may be associated to thyroid cancer risk, particularly in women. Experimental studies have documented thyroid cancer induction by elevation of endogenous TSH, although in a small number of animals. Iodine deficiency associated with carcinogenic agents and chemical mutagens will result in a higher incidence of thyroid malignancy. Inadequate low iodine intake will result in increased TSH stimulation, increased thyroid cell responsiveness to TSH, increased thyroid cell EGF-induced proliferation, decreased TGFbeta 1 production and increased angiogenesis, all phenomena related to promotion of tumor growth. Epidemiological studies associating iodine intake and thyroid cancer led to controversial and conflicting results. There is no doubt that introduction of universal iodine prophylaxis in population previously in chronic iodine-deficiency leads to a changing pattern of more prevalent papillary thyroid cancer and declining of follicular thyroid cancer. Also anaplastic thyroid cancer is practically not seen after years of iodine supplementation. Iodine excess has also been indicated as a possible nutritional factor in the prevalence of differentiated thyroid cancer in Iceland...

Thyroid cancer in children is usually rare, but in the individuals exposed to radiation risk of disease increases considerably. After the Chernobyl accident in 1986, an over 10-fold maximal elevation in the incidence of thyroid cancer was registered about a decade later, cumulatively resulting in more than a thousand of newly diagnosed cases in children who lived in the territories of Belarus, Russia, and Ukraine affected by radioactive fallouts. Experience from the epidemic substantially promoted knowledge in clinical pediatric oncology, pathology and basic sciences. This article overviews epidemiology, clinical features, results of treatment and follow-up of childhood patients with radiation-induced Chernobyl thyroid cancer in comparison to sporadic cases diagnosed at present. In addition, we discuss general issues of pathology and molecular findings in childhood thyroid carcinomas.

Positron emission tomography (PET) is a rapidly evolving imaging modality that has gained widespread acceptance in oncology, with several radionuclides applicable to thyroid cancer. Thyroid cancer patients have been studied most commonly using 18F-Fluorodeoxyglucose (FDG)-PET, with perhaps the greatest utility being the potential localization of tumor in differentiated thyroid cancer (DTC) patients who are radioiodine whole body scan (WBS) negative and thyroglobulin (Tg) positive. Also of value is the identification of patients unlikely to benefit from additional 131I therapy and identification of patients at highest risk of disease-specific mortality, which may prompt more aggressive therapy or enrollment in clinical trials. Emerging data suggest that PET/CT fusion studies provide increased accuracy and modify the treatment plan in a significant number of DTC cases when compared to PET images alone. However, studies documenting improvements in survival and tumor recurrence attributable to FDG-PET imaging in thyroid cancer patients are lacking. Specific case examples of thyroid cancer patients who appear to have benefited from FDG-PET imaging do exist, while less data are available in the setting of anaplastic or medullary thyroid carcinoma. This article reviews the utility and limitations of FDG-PET in DTC management...

This review is focused on "new drugs" that might be developed for thyroid cancer treatment. Thyroid cancer is frequently associated to the activation of specific protein (RET, BRAF) and lipid [PI(3)K] kinases. There is good evidence that these genetic lesions are causative events in thyroid cancer initiation or progression. Therefore, novel compounds able to target these kinases might be useful for thyroid cancer treatment. The power of this approach is witnessed by the examples of BCR-ABL, c-KIT and EGFR inhibitors in the treatment of chronic myelogenous leukemia (CML), gastro-intestinal stromal tumors (GIST) and non-small cell lung carcinoma (NSCLC).

The amplification of thyroglobulin (TG) mRNA in peripheral blood of patients with thyroid cancer has been studied for almost one decade, but its real contribution for diagnosis of cancer relapse has not yet been established. In the present paper we report the case of a patient with papillary thyroid cancer with undetectable stimulated serum thyrogobulin levels after thyroid ablation. Follow-up showed the presence of high titers of anti-thyroglobulin antibodies and the presence of TG mRNA in a peripheral blood sample, while cervical ultrasound and thorax and cervical computerized tomography were negative. Reinvestigation confirmed lymph node metastases. Anti-TG antibodies progressively decreased after surgery for metastatic lymph nodes resection followed by radioiodine therapy. Although our recent findings show that patients with positive TG mRNA do not have increased risk of cancer recurrence after 24 months of follow-up, the presence of TG mRNA along with high anti-TG antibodies were important indicators that determined further extensive investigation of tumour relapse in this patient, since positron emission tomography scan was not available at our Institution. A methodological standardization that can distinguish specific from non-specific TG mRNA amplification might be of great interest for the follow-up of differentiated thyroid cancer...

The aims of these recommendations were to develop clinical guidelines for evaluation and management of patients with differentiated thyroid cancer applicable to Latin American countries. The panel was composed by 13 members of the Latin American Thyroid Society (LATS) involved with research and management of thyroid cancer from different medical centers in Latin America. The recommendations were produced on the basis of the expert opinion of the panel with use of principles of Evidence-Based Medicine. Following a group meeting, a first draft based on evidences and the expert opinions of the panel was elaborated and, later, circulated among panel members, for further revision. After, this document was submitted to the LATS members, for commentaries and considerations, and, finally, revised and refined by the authors. The final recommendations presented in this paper represent the state of the art on management of differentiated thyroid cancer applied to all Latin American countries.

OBJECTIVE:The purpose of this study was to determine whether familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic thyroid cancer. SUBJECTS AND METHODS: We compared the clinical behavior and outcome of 16 subjects with FNMTC from 7 unrelated kindred with those observed in 160 subjects with sporadic PTC (SPTC) from our database. RESULTS: The only different baseline characteristics observed between both groups were: bilateral malignancy, 38% vs. 24%, respectively (p = 0.03), and lymph node metastasis, 56.2% vs. 39%, respectively (p = 0.01). Considering the outcome, in the FNMTC, 9 (56.2%) patients were rendered free of disease, one patient died from thyroid cancer (6%), and 6/16 (37.5%) had persistent disease. In the SPTC Group, 87 (54%) patients were considered free of disease, 11 (7%) died due to PTC, and 62 (38%) had persistent disease (p = ns). CONCLUSIONS: Despite the higher incidence of lymph node metastasis in FNMTC patients this situation seemed not to alter the compared outcome.

Objective The frequency of thyroid nodules accompanying Graves’ disease and the risk of thyroid cancer in presence of accompanying nodules are controversial. The aim of this study was to evaluate the frequency of thyroid nodules and the risk of thyroid cancer in patients operated because of graves’ disease. Subjects and methods Five hundred and twenty-six patients in whom thyroidectomy was performed because of Graves’ disease between 2006 and 2013 were evaluated retrospectively. Patients who had received radioactive iodine treatment and external irradiation treatment in the neck region and who had had thyroid surgery previously were not included in the study. Results While accompanying thyroid nodule was present in 177 (33.6%) of 526 Graves’ patients, thyroid nodule was absent in 349 (66.4%) patients. Forty-two (8%) patients had thyroid cancer. The rate of thyroid cancer was 5.4% (n = 19) in the Graves’ patients who had no nodule, whereas it was 13% (n = 23) in the patients who had nodule. The risk of thyroid cancer increased significantly in presence of nodule (p = 0.003). Three patients had recurrence. No patient had distant metastasis. No patient died during the follow-up period. Conclusions Especially Graves’ patients who have been decided to be followed up should be evaluated carefully during the follow-up in terms of thyroid cancer which may accompany. Arq Bras Endocrinol Metab. 2014;58(9):933-8

Introduction Primary hyperparathyroidism (PHPT) is associated with several cancer types, including papillary thyroid carcinoma (PTC). Objective To explore further the relation between PHPT and PTC. Methods By considering patients with PHPT as extra-suspicious for PTC, we studied an exemplar group of patients with PHPT with a small (1 cm) thyroid nodule, which was negative in preoperative cytologic examination. During parathyroidectomy, a frozen section biopsy of the thyroid nodule confirmed PTC, as did the final surgical specimen, revealing that the preoperative cytology was false-negative. Additionally, relevant reports retrieved from the English literature addressing thyroid cancer and hyperparathyroidism were reviewed and processed. Results Four patients with PHPT were studied. Three had a multifocal thyroid disease, and three had neck lymph node metastasis. Processing previous report data supported an association between PHPT and PTC. Although thyroid nodularity among patients with PHPTwas similar to the general population, PTC incidence was higher. This was true also for patients with secondary hyperparathyroidism. Conclusions This study emphasized that PHPT should be considered as a noteworthy risk factor for PTC. Fine needle aspiration of a thyroid nodule is the most valuable diagnostic procedure for thyroid cancer. Yet...

Background: While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient mice. Genetically engineered models of papillary and undifferentiated (anaplastic) thyroid carcinoma (PTC and ATC) are immunocompetent; however, slow and stochastic tumor development hinders high-throughput testing. Novel models of PTC and ATC in which tumors arise rapidly and synchronously in immunocompetent mice would facilitate the investigation of novel therapeutics and approaches.

Background: Mouse models of metastatic human cancers are important tools in preclinical studies for testing new systematic therapies and studying effectors of cancer metastasis. The major drawbacks of current mouse models for metastatic thyroid cancer are that they have low metastasis rates and do not allow in vivo tumor detection. Here, we report and characterize an in vivo detectable metastasis mouse model of human thyroid cancer using multiple thyroid cancer cell lines.

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells...

Thyroid nodules are common in clinical practice and the incidence of thyroid cancer is increasing throughout the world. Certainly, an important factor for the increase of the incidence is the use of ultrasound and PAFF. The identification of genetic polymosphism is important for understanding the potential mechanisms involved in thyroid carcinogenesis. We hypothesized that polymorphisms of xenobiotic enzyme system (CYP1A1, GSTM1 and GSTT1) and the common germline polymorphism of TP53 gene at codon 72 may be associated with the risk of thyroid cancer. To evaluate the role of such polymorphisms, we investigated 122 cases of thyroid nodules, classified according to the following: 35 malignant neoplasic nodules (MNN), 20 benign neoplasic nodules (BNN) and 67 non-neoplasic nodules (NNN) compared with 134 controls of the healthy individuals randomly selected. The PCR-RFLP was used in the analysis of the CYP1A1m1 and CYP1Am2 genotypes; the multiplex PCR was used in the deletion analysis of the GSTM1 and GSTT1; and for the determination of the polymorphism in the gene TP5372, the samples were submitted to conventional PCR reaction. We included case-control studies that compare the incidence of germline polymorphism of TP5372 in patients with thyroid cancer by DerSimonian-Laird method. Our results demonstrated that CYP1A1m1 and CYP1A1m2 genotypes were frequent not only as neoplasic thyroid nodules and non-neoplasic thyroid nodules but also in the control group...

Thyroid nodules are frequent findings, especially when sensitive imaging methods are used. Although thyroid cancer is relatively rare, its incidence is increasing, particularly in terms of small tumors, which have an uncertain clinical relevance. Most patients with differentiated thyroid cancer exhibit satisfactory clinical outcomes when treatment is appropriate, and their mortality rate is similar to that of the overall population. However, relapse occurs in a considerable fraction of these patients, and some patients stop responding to conventional treatment and eventually die from their disease. Therefore, the challenge is how to identify the individuals who require more aggressive disease management while sparing the majority of patients from unnecessary treatments and procedures. We have updated the Brazilian Consensus that was published in 2007, emphasizing the diagnostic and therapeutic advances that the participants, representing several Brazilian university centers, consider most relevant in clinical practice. The formulation of the present guidelines was based on the participants' experience and a review of the relevant literature.

OBJECTIVE: The present study aimed to emphasize the necessity and significance of thyroidectomy by determining the prevalence of incidental thyroid cancer in the cases that underwent surgical intervention for the treatment of benign thyroid disease. SUBJECTS AND METHOD: Thyroidectomy was performed in 443 cases including those with benign multinodular goitre (BMNG) or toxic adenoma or toxic multinodular goitre. Diagnosis was made based on routine physical examination, laboratory analyses, imaging methods and postoperative histopathological findings of the cases. RESULTS: The mean age of the cases was 45.5 (19-68) years and 72.5% (n = 321) were female. The most common clinical diagnosis prior to the surgery was BMNG (n = 428, 96.6%). While BMNG was determined to be the most common histopathological diagnosis after thyroidectomy at a rate of 81.7% (n = 362), the rate of thyroid cancer was found to be 14% (n = 81). The prevalence ofpapillary cancer was 84% (n = 56), whereas it was 4% (n = 4), 1% (n = 1) and 0.0% (n = 0) for medullary, follicular and anaplastic cancers, respectively. Papillary cancer was also the most common type of thyroid cancer between genders. As compared to gender, there was no statistically significant difference in terms of distribution of age among general...